In the whole world in 2013, the number of HIV-1-infected people was about 35 million and the number of newly HIV-1-infected people was about 2.1 million; HIV-1 infection is still globally a major public health problem.
However, current anti-HIV-1 drugs can suppress HIV-1 proliferation but cannot eliminate HIV-1-infected cells from the body of infected people. Hence, HIV-1-infected people must take anti-HIV-1 drugs over a lifetime, posing problems of the chronic toxicity due to the long-term use of these anti-HIV-1 drugs and the appearance of drug-resistant HIV-1. Thus, there is now an increased need for the development of a radical treatment for HIV-1 infection. The medical cost per person with HIV-1 infection is said to be about 1 million dollars when the treatment period is assumed to be about 40 years, and such high medical cost becomes a socially major problem; there is a world-wide need for the development of a radical treatment for HIV-1.
The main cause for the fact that the complete cure of HIV-1 infection is difficult is the presence of HIV-1 latently infected cells. The latently infected cells are mainly HIV-1-infected cells derived from resting memory CD4+ T cells having a long life length; HIV-1 is present as proviral DNA in genomic DNA in these cells, and HIV-1 particles or HIV-1 proteins are little produced in a state free of cell activating stimuli, such as a proliferative stimulus; however, the activating stimuli are given to start HIV-1 production. Most of current anti-HIV-1 drugs can suppress HIV-1 production since they target HIV-1-derived enzymes, but cannot decrease the number of HIV-1 latently infected cells. Thus, to establish a radical treatment of HIV-1, the development of a treatment method targeting HIV-1 latently infected cells is needed.
A histone deacetylase (HDAC) inhibitor, affecting gene expression by suppressing the action of histone deacetylase to cause the hyperacetylation of histone, exerts an antitumor effect by changing the expression of an oncogene or a tumor suppressor. Some HDAC inhibitors are each already in the early stage of clinical development as a monotherapy or a combination therapy as a method for treating solid and hematological tumors.
There is known to be a relationship between chronic infection and carcinogenesis, e.g., hepatitis C virus infection and liver cell carcinoma, and Helicobacter pylori infection and stomach cancer. This is considered to involve that chronic inflammation has molecular mechanisms in common with cancer, such as the activation of an inflammatory signaling system and the induction of expression of various genes.
It has recently been reported that some HDAC inhibitors, such as entinostat and vorinostat activate HIV-1 latently infected cells (reservoir cells) to induce HIV-1 production. (Ricky W. Johnstone, Nature Reviews Drug Discovery 1, 287-299 (1 Apr. 2002))
JP Patent Publication (Kokai) No. 10-152462 A and JP Patent Publication (Kohyo) No. 2007-527362 A and Qing-Wei Zhang and Jian-Qi Li, Bull. Korean Chem. Soc. 2012, Vol. 33, No. 2 535 (http://dx.doi.org/10.5012/bkcs.2012.33.2.535) state that benzamide derivatives, such as entinostat and chidamide, as HDAC inhibitors are useful as therapeutic and improving agents for malignant tumor, autoimmune disease, dermatologic disease, and parasitic infection.
There has not previously been any report of the specific cell death-inducing effect of entinostat on HIV-1-infected human mononuclear cells.